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Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors

  • Alberto Minassi*
    Alberto Minassi
    Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, Novara 28100, Italy
    *Tel: +39 0321375843. E-mail: [email protected] (A. Minassi).
  • Federica Rogati
    Federica Rogati
    Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, Novara 28100, Italy
  • Cristina Cruz
    Cristina Cruz
    VivaCell Biotechnology SL. Parque Científico Tecnológico, Rabanales 21. Edificio Centauro, 14014 Córdoba, Spain
  • M. Eugenia Prados
    M. Eugenia Prados
    VivaCell Biotechnology SL. Parque Científico Tecnológico, Rabanales 21. Edificio Centauro, 14014 Córdoba, Spain
  • Nuria Galera
    Nuria Galera
    VivaCell Biotechnology SL. Parque Científico Tecnológico, Rabanales 21. Edificio Centauro, 14014 Córdoba, Spain
    More by Nuria Galera
  • Carla Jinénez
    Carla Jinénez
    Maimonides Biomedical Research Institute of Córdoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    Department of Cellular Biology, Physiology and Immunology, University of Cordoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    University Hospital Reina Sofía, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
  • Giovanni Appendino
    Giovanni Appendino
    Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, Novara 28100, Italy
  • M. Luz Bellido
    M. Luz Bellido
    VivaCell Biotechnology SL. Parque Científico Tecnológico, Rabanales 21. Edificio Centauro, 14014 Córdoba, Spain
  • Marco A Calzado
    Marco A Calzado
    Maimonides Biomedical Research Institute of Córdoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    Department of Cellular Biology, Physiology and Immunology, University of Cordoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    University Hospital Reina Sofía, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
  • Diego Caprioglio
    Diego Caprioglio
    Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, Novara 28100, Italy
  • , and 
  • Eduardo Muñoz*
    Eduardo Muñoz
    Maimonides Biomedical Research Institute of Córdoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    Department of Cellular Biology, Physiology and Immunology, University of Cordoba, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    University Hospital Reina Sofía, Avenida Menendez Pidal s/n, 14004 Cordoba, Spain
    *Tel: +34 957213766. E-mail: [email protected] (E. Muñoz).
Cite this: J. Nat. Prod. 2018, 81, 10, 2235–2243
Publication Date (Web):October 10, 2018
https://doi.org/10.1021/acs.jnatprod.8b00514
Copyright © 2018 American Chemical Society and American Society of Pharmacognosy

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    Abstract

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    Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.

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    • Table S1 (activity against transcription factors) and original spectroscopic data for the novel compounds (PDF)

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    Cited By

    This article is cited by 11 publications.

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    2. Jin Wang, Dong-Bo Wang, Li-Li Sui, Tian Luan. Natural products-isoxazole hybrids: A review of developments in medicinal chemistry. Arabian Journal of Chemistry 2024, 17 (6) , 105794. https://doi.org/10.1016/j.arabjc.2024.105794
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    5. María Eugenia Prados, Carmen Navarrete, Adela García-Martín, Isabel Lastres-Cubillo, Francisco Ponce-Díaz, José Martínez-Orgado, Eduardo Muñoz. VCE-005.1, an hypoxia mimetic betulinic acid derivative, induces angiogenesis and shows efficacy in a murine model of traumatic brain injury. Biomedicine & Pharmacotherapy 2023, 162 , 114715. https://doi.org/10.1016/j.biopha.2023.114715
    6. Xiyue Wang, Qingyun Hu, Hui Tang, Xinhui Pan. Isoxazole/Isoxazoline Skeleton in the Structural Modification of Natural Products: A Review. Pharmaceuticals 2023, 16 (2) , 228. https://doi.org/10.3390/ph16020228
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    8. Ziqi Zhou, Ji-Won Choi, Joon Yeon Shin, Dong-Uk Kim, Bitna Kweon, Hyuncheol Oh, Youn-Chul Kim, Ho-Joon Song, Gi-Sang Bae, Sung-Joo Park. Betulinic Acid Ameliorates the Severity of Acute Pancreatitis via Inhibition of the NF-κB Signaling Pathway in Mice. International Journal of Molecular Sciences 2021, 22 (13) , 6871. https://doi.org/10.3390/ijms22136871
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